Noble French Roman Catholic family that played a major role in French politics during the Reformation .
Claude de Lorraine (14961550) was created the 1st duke de Guise in 1527 for his service to Francis I in the defense of France. Claude's sons François, 2nd duke de Guise , and Charles, cardinal de Lorraine (15241574), gained great power during the reign of Francis II . Supported by Spain and the papacy, their persecution of the Huguenots led to the unsuccessful Amboise Conspiracy (1560), an attempted assassination of the leaders of the Guise party and transfer of power to the house of Bourbon . The Guise-led massacre of a Huguenot congregation at Vassy precipitated the Wars of Religion , in which Henri I, 3rd duke de Guise , was a prominent leader. Charles de Lorraine, 4th duke de Guise (15711640), lived through the rapid decline of the family's power. Henri II, 5th duke de Guise , tried unsuccessfully to revive the family's power; the direct line expired with the death of his grand-nephew in 1675.